Spinal cord injury (SCI), depending on its location and severity, disrupts neural control of the bladder, resulting in significant morbidity and reduced quality of life. Beyond neural impairment, SCI-induced bladder dysfunction is driven by neuroinflammation, oxidative stress, and extracellular matrix remodelling. Previous studies have highlighted excessive activation of poly(ADP-ribose) polymerase 1 (PARP1), a key enzyme involved in DNA repair, following SCI. Inosine, a purine nucleoside with neuroprotective properties, has been shown to improve functional recovery after neurological injury, raising interest in its potential role in bladder function. Here, we investigate bladder alterations after SCI, focusing on mitochondrial dysfunction, oxidative stress, and DNA damage, and evaluate the effects of inosine on PARP1 activation and bladder function.

A murine model of SCI was used to examine bladder responses during the spinal shock phase and over a 4-week period. Urodynamic investigations (UDI) were performed in awake animals using an optimised setup incorporating an infrared (IR) camera for precise detection of micturition onset, enabling longitudinal evaluation of bladder function. Bladder alterations were characterized by inflammatory mediator profiling, comet assay and immunofluorescence to assess DNA damage and repair, and measurement of mitochondrial reactive oxygen species (ROS) using MitoSOX-based flow cytometry in dissociated bladder cells, complemented by histological analyses. Inosine was administered via daily intraperitoneal injections, and its effects were compared with untreated SCI and sham controls. The role of PARP1 was further investigated using both pharmacological inhibition with olaparib and genetic deletion in PARP1 knockout mice.

SCI induced rapid and sustained bladder dysfunction, characterized by increased detrusor pressure amplitudes and persistent non-voiding contractions compared to sham controls. Early after injury, involuntary pressure spikes were observed during the spinal shock phase, followed by sustained high-pressure voiding associated with detrusor–sphincter dyssynergia. These functional alterations were accompanied by vascular and inflammatory responses that promoted mitochondrial dysfunction and increased mitochondrial ROS production, resulting in metabolic stress and DNA damage. DNA damage was more pronounced in wild-type mice but attenuated in PARP1-deficient animals, supporting a role for PARP1 in linking oxidative stress to cellular injury. Pharmacological inhibition of PARP1 with olaparib exacerbated early bladder instability, whereas inosine treatment reduced non-voiding contraction frequency and detrusor pressure amplitude. Inosine-treated animals also showed improved bladder capacity, distensibility, and reduced maladaptive remodeling, alongside decreased oxidative stress and DNA damage.

These findings indicate that bladder dysfunction after SCI is driven not only by neural disruption but also by early mitochondrial dysfunction and oxidative stress–mediated DNA damage, with PARP1 acting as a central mediator linking metabolic stress to cellular injury. Inosine attenuates this injury cascade by reducing oxidative stress and DNA damage, leading to improved bladder function. Targeting these early molecular pathways may therefore alter disease progression after SCI.

Targeting early metabolic and DNA damage pathways, including modulation of PARP1 activity and inosine treatment, represents a promising strategy to prevent or delay the onset of neurogenic bladder dysfunction following SCI.

Continence 19S (2026) 102498
DOI: 10.1016/j.cont.2026.102498